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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5409_Библиотеки_им_академика_М_И_Перельмана.pdf
Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Exogenous sources of ROS include radiation, drugs and chemicals, heavy metals, pollutants, viruses
etc. Exposure to ionizing radiation (IR) can directly disrupt atomic structures producing chemical and
-
biological changes or it can lead to production of ROS such as e
,•OH, H•, H2, and H2O2 by radiolysis
aq
of water. IR also stimulates inducible nitric oxide synthase (NOS) activity in cells generating nitric ox-
•
ide (NO
). Indirect effects of low linear energy transfer (LET) IR such as γ-rays and X-rays modulates
the extent of production of these species. As water content in the cells is high these free radicals and
•-
electrons react with it and other oxygen molecules to produce superoxide anion radical (O
•
highly reactive and can further react with nitric oxide (
NO) to produce peroxynitrite anion (ONOO−).
) which is
2
The ROS generated ultimately in turn attack other critical molecules (Azzam et al., 2012).
Simultaneous induction of several ROS-producing pathways and enzymes by biological agents such
as virus can cause oxidative stress. Respiratory viruses, hepatitis C virus (HCV), human papailioma
virus (HPV) triggers enzymes like the nicotinamideadenine dinucleotide phosphate oxidases (NADPH
oxidases, Nox) and xanthine oxidase (XO), cytochrome P450 2E1 (CYP2E1) and ER oxidoreductin
1α (Ero1α). Production of ROS is also induced by viral proteins. One mechanism of ROS production
induced by HCV involves localization of its core proteins on mitochondrial membrane or by binding
to heat shock protein 60 (Hsp60) in mitochondrial matrix. This causes accumulation of calcium ions
in mitochondria which alters normal functioning of the respiratory chain (Marco et al., 2013; Ivanov
et al., 2017; Khomich et al., 2018). Chronic HCV infection leads to steatosis and the accumulated free
fatty acid enhance production of reactive oxygen species (ROS), causing mitochondrial dysfunction and
endoplasmic reticulum stress (Irshad et al., 2017).
Both natural and synthetic compounds can be factors for cancer development. Certain chemicals or
combination of chemicals can induce carcinogenesis upon exposure (Luch, 2005). The mode of absorption and distribution of these compounds to several tissues depends on their physicochemical properties
(King et al., 1995; van Leeuwen & Zonneveld, 2001). Chemical carcinogens can be classified as genotoxic carcinogens i.e. they directly react with DNA through the formation of covalent bonds resulting in
DNA-carcinogen complexes called as DNA adducts or nongenotoxic carcinogens i.e. they do not react
directly with DNA. They can be cytotoxic or mitogenic in function. Mitogenic compounds induce cell
proliferation in target tissue through interaction with a specific cellular receptor and cytotoxic carcinogens cause cell death in susceptible tissues (Cohen 1991; Cohen et al., 1992; Butterworth & Bogdanffy,
1999; Luch, 2005). The dead cells/necrotic cells are removed by cells of the immune system through a
series of biochemical processes which leads to production of ROS (Lutz, 1998; Ohshima et al., 2005).
Genotoxic carcinogens usually require metabolic activation of the parent compound to a highly reactive
compound. The reactive compound interacts with cellular DNA or enzymes involved in DNA repair
causing a mutation in the DNA (Miller, 1970). The metabolic activation usually takes place in the liver
where cytochrome P450 is in abundance. Nitrosamines, carbon tetrachloride (CCl
metabolically activated and act like free radicals, significantly increase superoxide radical (O
), aflatoxins, etc. are
4
•−
) concentra-
2
tion in the liver and damage various biological systems (Recknagel et al., 1989; Nordmann et al., 1992).
Diethylnitrosamine (DEN), a thoroughly studied carcinogen is metabolically activated to produce
α-hydroxyl nitrosamine in liver (Figure 32.1). The hydroxylation process is carried out by cytochrome
P2E1; an isozyme of the P450 complex (Sharan and Wary, 1992; Verna et al., 1996; Wary and Sharan,
1999). The electrophilic ethyldiazonium ion reacts with DNA bases to form promutagenic adducts
6
-ethyl deoxy guanosine and O4 and O2- ethyl deoxy thymidine that can produce DNA chain damage,
O
depurination or binding to DNA increasing the ROS pool. Exposure to DEN also caused an increase
level of 8-OHdG and its generation was at an early stage of exposure which reflects the oxidative dam-
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Figure 1. Biotransformation of DEN and mechanism of DNA-adduct formation. (Source: Verna 1996,
Wary & Sharan 1991, Sharan & Wary 1992).
age to DNA (Nakae et al., 1997). 8-OHdG can pair with both cytosine and adenine causing a GC to TA
transversion. Mutated oncogenes and tumour suppressor genes contain these nucleotides (Shibutani,
et al., 1991; Cheng et al., 1992; Grollman & Moriya, 1993). During DNA replication, OH8dG is incorporated into the daughter strand complementing dC or dA on the template strand resulting in AT to
CG transversions (Cheng et al., 1992; Demple & Harrison, 1994). DEN caused Ha-ras, B-raf and Ctn-
nb1mutations (Tolba et al., 2015). Metabolic activation of DEN leads to formation of lipid radicals in
the whole body of exposed animals and also caused lipid peroxidation. The lipid radicals are generated
through microsomal metabolism. This indicates that free radical intermediates play an important role in
the initiation of hepatic carcinogenesis by DEN (Bartsch et al., 1989; Yamada et al., 2006).
ROS are important for cellular homeostasis. At low or regulated levels, ROS are involved in many
vital physiological processes. They serve as signaling molecules and response to growth factor stimulation and control of inflammatory responses. They are responsible to regulate numerous physiological
and cellular processes including cell differentiation, proliferation, apoptosis, and adaptation to hypoxia,
cytoskeletal regulation, migration and contraction (Krause, 2007; Finkel, 2011; Holmstrom & Finkel,
2014; Schieber & Chandel, 2014). Under normal physiological conditions, ROS are steadily maintained
to prevent cells from oxidative damages. The stable concentration of ROS in cells is maintained by detoxifying enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), Phase
II enzymes (e.g., glutathione transferase, NAD(P)H: quinone reductase, UDP-glucuronosyltransferases)
that specifically scavenge different kinds of ROS. The nonenzymatic component which includes scavenger molecule glutathione, beta-carotene, vitamin A, ascorbic acid (vitamin C) and alpha-tocopherol
(vitamin E) are also involved in maintaining redox equilibrium (Mataix et al., 1998). Cellular levels of
reactive oxygen species can increase due to overproduction and diminished elimination. This can be
due to increased metabolic activity, mitochondrial dysfunction, oncogene activation which enhanced
metabolism or loss of tumor suppressor which diminish ROS elimination (Trachootham et al., 2009).
Exposure to environmental factors can also lead to increase in cellular ROS. The incidence of cancer is
seen to be directly linked to exposures to environmental factors. Most environmental factors can directly
or indirectly generate ROS which plays an important role in carcinogenesis. At the initiation stage of
carcinogenesis, ROS is involved in changing the genetic makeup of cell which occurs through formation of oxidative DNA adducts leading to mutations (Dizdaroglu, 1992; Demple & Harrison, 1994; Lu
et al., 2001; Odyuo &Sharan, 2005; Bhattarcharjee & Sharan, 2008). DNA stand breakage, nucleotide
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369
Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
modifications, deoxyribose modification and DNA cross-linking are results of ROS reaction with DNA.
If the oxidative damages to DNA are not repaired before replication processes, then it will lead to further
mutation in DNA, genome instability, more errors in replication and cell death (Marnett, 2000; Cooke,
2003; Klaunig & Kamendulis, 2004; Valko et al., 2006). Disruption or activation of genes responsible
for regulation of cell growth, survival, and senescence allows mutated cells to proliferate leading to accumulation of preneoplstic cells within a tissue (Mehta, 1995; Gomes-Carneiro et al., 1997). Alteration
in the expression of cytokine growth factors e.g. tumour necrosis factor-α, interleukins etc. increases cell
2+
proliferation. ROS can influence Ca
2+
of Ca
ions within the intracellular area, this can results in activation of proto-oncogenes such as c-fos,
channels/pumps/exchangers and can lead to increase in concentration
c-jun, c-myc or activated protein kinase C (PKC), Notch1/Nrf2 and other signalling pathways involved
in cell migration and invasion leading to cancer progression (Klaunig & Kamendulis, 2004; Wu, 2006;
Strzelczyk & Wiczkowski, 2012; Zhang et al., 2016; Aggarwal et al., 2019).
Figure 2. Reactive oxygen Species (ROS): Sources, roles in cellular function and their implications on
cancer (Matés &Sánchez-Jiménez, 1999 with modification)
INFLAMMATION AND CANCER
Inflammation is an immune response that is triggered when the host is exposed to certain external
stimulus. Activation of inflammatory signals occurs to repair tissues damage and eliminate a damaging agent. Upon exposure to infections, radiations or chemicals, inflammatory cells, macrophages and
mast cells that release cytokines like TNF-α, IL-1β, IL-6 and pro inflammatory chemokines like IL-8,
MCP-1,MIP-1α stimulate attraction of circulating leukocytes to the site of inflammation to eliminate
the pathogen, initiate healing and generate immunological memory. This type of inflammation is acute
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
inflammation and it is a physiological process and a host defensive response. Persistent inñammation
due to continuous exposure to infections/insults leads to chronic inñammation causing further damage
and increasing the risk of cancer. About 15-20% of all death from cancer worldwide is associated with
chronic inflammation caused by infection or physicochemical agents (Prete et al., 2011; Korniluk et al.,
2017; Zhanget al., 2017; Monkkonen & Debnath, 2018). Hepatocellular carcinoma (HCC) can arise due
to chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). Infection with Helico-
bacter pylori can lead to chronic inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC)
and increase the risk of most gastric cancers and colorectal cancer, tobacco smoking leads to chronic
airway irritation and inflammation and can promote lung cancer.
DEN primarily affects the liver and can damage intracellular organelles like mitochondria, endoplasmic reticulum and cause hepatocyte death (Cayama et al., 1978; Lim, 2002; Karin, 2006; Hadem et al.,
2014; 2016; Basaiawmoit et al., 2016). DEN induced hepatocellular carcinoma (HCC) arise due to an
exchange of inflammatory signals between dying hepatocytes and myeloid cells. The dying hepatocytes
release byproducts such as HMGB1, interleukin-1 alpha (IL-1α) which causes activation of Kuffer cells
(Scaffidi et al., 2002; Sakurai et al., 2008). Rapid accumulation of TNF-α was seen upon administration
of DEN (Maeda et al., 2005) and the process of carcinogenesis is mainly associated with the release of
this cytokine (Sethi et al., 2008; Balkwill, 2009). Inflammation has been regarded as the ‘seventh hallmark of cancer’ and key mediator between the two is TNF-α (Mantovani et al., 2008; Mantovani, 2009).
INFLAMMATORY CYTOKINE TUMOUR NECROSIS
FACTOR α (TNF-α) IN CARCINOGENESIS
TNF-α is a proinflammatory cytokine with a molecular weight of 17 kDa. In humans, TNF-α is expressed
as a 27-kDa protein that is proteolytically cleaved by a metalloprotease TNF α-converting enzyme
(TACE), resulting in a 17-kDa molecule (Black et al., 1997). They are released mainly from activated
macrophages, astroglia, microglia, Langerhans cells, and Kupffer cells though it is also produced by
many different types of cells in the body. TNF belongs to the TNF/TNFR superfamilies that are involved
in signalling pathways for cell proliferation, survival and differentiation and TNF-α is reported to play a
role in many clinical conditions (Beutler 1993, Higashi et al., 1995, Risberg et al., 1991, Strieter et al.,
1993, Licinio and Wong, 1996, Cressman et al., 1996, Muller-Ladner, 1996).
Various experimental studies carried out on different models by Kitagawa et al. (1984), Komori et al.
(1993), Fujiki & Suganuma (1994), Sueoka et al. (1997), strongly indicate that TNF-α is an endogenous
carcinogenic inflammatory cytokine. Independent studies carried out by Kishimoto (1989) and Suganuma
et al. (2002), found that the signaling sequence in carcinogenesis is initiated from TNF-α through IL-1
to IL-6 and back to TNF- α, suggesting that TNF- α is the master cytokine in tumor promotion. TNF-α
is involved in different stages of carcinogenesis right from initiation by inducing genetic changes in the
cells, (Komori et al., 1993, Suganuma et al., 2002) metastasis by stimulating certain chemokines, such as
CXCL1 and CXCL2 (Acharyya et al., 2012) and more significantly in progression through the activation
of NF-κB transcription factor which is required for gene expression of TNF-α and other proinflammatory
cytokines (Sen & Baltimore, 1986).
Depending on the cell type there are different signalling mediators involved for TNF-α induced signaling pathway. The binding of TNF to its receptor can induce either cell survival or cell death. There
are more than 20 members of TNFR family categorized into two broad groups based on the presence
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Figure 3. Exposure to DEN activates specific intracellular programmes to induce programme cell death
(PCD). Compensatory proliferation of hepatocytes occurs to maintain liver integrety which can lead to
the development of HCC. (Source: Papa et al., 2009).
or absence of a death domain. The traditional TNF signal cascade starts with the binding of TNF-α to
TNFR1 (p55, p60, CD120a) and the recruitment of TNF receptor associated death domain (TRADD),
TNF receptor associated factor 2 (TRAF2), and receptor interacting protein (RIP 1) to form complex I.
Complex I can activate mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases
(ERK), and c-Jun N-terminal kinases (JNK) which in turn activates activated protein 1 (AP-1), complex
I can also activate NF-κB (Sen and Baltimore, 1986; Westwick et al., 1994; Karin 1995; Karin et al.,
1997). TNFR1 (p55, p60, CD120a) and Fas (Apo-1, CD95) recruits TRADD, Fas-associated death
domain protein (FADD) and procaspase-8 to form complex II which activates several effector caspases
that are responsible for apoptosis (Boldin et al., 1995; Chinnaiyan et al., 1995; Ashkenazi & Dixit, 1998;
Rathmell & Thompson, 1999) (Figure 32.4). Recruitment of TRAF2 by other TNF receptor (TNFR)related members like TNFR2 (p75, p80), CD30 and Ox40 also regulates NF-κB and AP-1(Rothe et al.,
1994; 1995; Gedrich et al., 1996; Arch & Thompson, 1998; Arch et al., 1998). Activation of transcription
factors NF-κB and AP-1 has been linked directly to cellular proliferation, survival and differentiation
(Arch & Thompson, 1999; Locksley et al., 2001).
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Figure 4. TNF-α signalling pathway for induced cell death programme and proliferation. (Source: Papa
et al. 2009).
NF-κB TRANSCRIPTION FACTORS SIGNALLING IN CELL PROLIFERATION
NF-κB group of transcription factors plays a crucial role in development, cell survival and are known
to be coordinators of inflammation and innate immunity (Hayden & Ghosh, 2004; Dutta et al., 2006).
These transcription factors recognise the κB motifs of DNA. NF-κB consists of homo and heterodimers
which composed of p50, p52, p65 and c-Rel. p50-p65 heterodimer also known as Rel A is the most
prominent form of NF-κB (Ghosh & Karim, 2002). Inhibitory I
NF-κB dimers and hold them in an inactive state in the cytoplasm. I
of the regulatory subunit IKK-γ and two catalytic subunits IKK-α and IKK-β can phosphorylate I
Phosphorylation of I
B leads to its poly-ubiquitination and subsequent proteolytic degradation, liberating
κ
NF-κB dimers to enter the nucleus and initiate transcription of genes with κB sites (Figure 32.5). Although
both catalytic IKK subunits are capable of inducing I
kinase than IKK-α, IKK-β mediates the majority of I
B phosphorylation, IKK-β is a more efficient IκB
κ
B phosphorylation in vivo (Ghosh & Karim, 2002).
κ
NF-κB activation is observed in many forms of cancer. Activated NF-κB is constitutively expressed
in tumour cells from breast, colon, blood neoplasm, pancreas and squamous cell carcinoma cell lines
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κ
B proteins are directly associated with
B kinase (IKK) complex consisting
κ
B.
κ
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Figure 5. NF-κB transcription factors activation in response to inflammatory cytokines. (Source: Scott
& Roifman, 2019 with modification).
(Kaltschmidt & Kaltschmidt, 2003). NF-κB plays an important role in tumour promotion since it is
the major activator of anti-apoptotic gene expression. NF-κB was shown to be instrumental in tumour
promotion in a colitis-associated cancer (CAC) model. NF-κB promotes production of cytokine IL-6
in myeloid cells that act as growth promoters for the pre-neoplastic enterocytes whereas in enterocytes
NF-κB activates anti apoptotic genes leading to proliferation of pre-malignant cells (Greten et al., 2004).
Pikarsky et al., (2004) study of hepatocellular carcinoma (HCC) in multidrug resistance 2 (Mdr2)knockout mice showed that NF-κB activation in heptocytes suppresses apoptosis of pre-malignant cells
and it is an inflammation-induced phenomenon secondary to parenchymal infiltration by inflammatory
cells (Kupffer cells). NF-kB activation is primarily induced by TNF-α through paracrine stimulation.
NF-κB is essential for tumour promotion and regulates multiple anti-apoptotic genes including cellular
inhibitors of apoptosis (cIAPs), caspase-8 inhibitor c-FLIP, members of the Bcl-2 family, A1/Bfl-1, Bclxl, TRAF2 and the zinc finger protein A20. Some act by either blocking the activity of death receptors
or the mitochondrial death pathway (Wajant et al., 2003). The crosstalk between the NF-κB and JNK
pathways is another mechanism by which NF-κB protects hepatocytes from TNF-α induced cell death.
NF-κB regulates transcription factors X-liked inhibitor of apoptosis (XIAP) and Growth arrest DNA
damage-inducible gene 45β (GADD45) as well as the antioxidant enzyme SOD2 that are linked to the
repression of JNK activity. NF-κB thus provides a connection between its activation and subsequent
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
suppression of ROS and tumour promotion and progression in TNF-α induced cell death (De et al.,
2001; Tang et al., 2001).
In the studies conducted by Maeda et al. (2005) Naugler et al. (2007) and Sakurai et al. (2008), where
they used DEN to induce HCC in mice, hepatocarcinogenesis occurs through the production of cytokine
that stimulates compensatory proliferation. Administration of DEN caused rapid accumulation of ROS
and elevated oxidative stress which mainly affects centrilobular (zone 3) hepatocytes where DEN is
metabolized (Yang et al., 1990). ROS accumulation caused hepatocyte death which results in the release
of IL-1α and other substances such as HMGB1, S100 calcium-binding proteins, purine metabolites or
heat-shock proteins from the dying cells (Karin & Greten, 2005). These substances caused activation of
Kupffer cells which induces rapid production of TNF-α and IL-6 and hepatocyte growth factor (HGF)
by stellate cells whose production depends on factors produced by Kupffer cells. TNF-α/IL-6 induced
program cell death (PCD) in hepatocytes but since the liver can regenerate due to its remarkable proliferative capacity, elevated hepatocyte death enhances compensatory proliferation and survival of genetically
altered cells. ROS accumulation also leads to JNK1 activation and c-jun expression. JNK1 activation
further contributes to ROS accumulation. JNK and c-jun are important contributors to hepatocyte proliferation and HCC development. Activation of NF-κB and AP-1 dependent via TNF-α stimulation thus
leads to cell proliferation (Papa et al., 2009).
PHYTOCHEMICAL-BASED ANTICANCER DRUG DEVELOPMENT
FROM PLANTS WITH EMPHASIS TO CANCER
Natural products are a source of new drugs and about 80% of drugs are from natural products or their
derivatives. Many areas of scientific specialization including botanical, phytochemical, biological, molecular techniques, pharmacology and high-throughput screening (HTS) are involved in drug discovery
from medicinal plants (Balunas & Kinghorn, 2005; Wassermann et al., 2015). Since the 1940s to date,
of the 175 small molecules, 85 or 48.6% are either natural products or directly derived from them are
approved anticancer agents (Newman & Cragg, 2016). Anticancer agents derived from plants currently
in clinical use are camptothecin (CPT), vinblastine, epipodophyllotoxins, taxanes, camptothecins, combretastatins and homoharringtonine (Balunas & Kinghorn, 2005; Cragg & Pezzuto, 2016). These plant
derived natural products can be classified into the following chemical groups: Aldehydes, Alkaloids,
Annonaceous acetogenins, Polyphenols (flavonoids and phenolics), Glycosides, Lignans, Lipids, Lipids (unsaponified), Nucleic acids, Polysaccharides, Proteins, Terpenoids. These phytochemicals exert
their anticarcinogenic effects by different mechanisms. Several alkaloids exhibit antiproliferation and
antimetastasis effects on various types of cancers both in vitro and in vivo (Lu et al., 2012). Elimination
of carcinogenic compounds by activating detoxifying enzymes is one way to prevent carcinogenesis
and many compounds like Glucosinolates and indoles, thiocyanates and isothiocyanates, phenols and
coumarins have been shown to play an important role in detoxification process (Keck & Finley, 2004).
Activation of nitrosamines into their highly reactive forms is blocked by ascorbate and phenols (Mirvish,
1981; Bartsch & Frank, 1996). Flavonoids and phenolic act as free radical scavengers and metal chelators
depending on their chemical structures. They act as antioxidants to reduce the oxidative stress produced
by some carcinogens, therefore improving cell survival (Rice et al., 1995; García et al., 2018) or they can
act as prooxidants inducing apoptosis and blocking cell proliferation. Flavonoids inhibit tumor growth
by inducing apoptosis of transformed cells; prevent angiogenesis and metastasis (Wenzel et al., 2000).
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Dietary polyphenols contribute to the prevention of cancer onset and development (Yao et al., 2004;
Porrini et al., 2005). Polyphenols can directly interact with specific steps and/or proteins responsible
for the regulation of apoptotic process such as the release of cytochrome c with subsequent activation of
caspases-9 and caspases-3 (Yao et al., 2004; Porrini et al., 2005), the increase of caspases-8 and t-Bid
levels, the down-regulation of Bcl-2 and Bcl-XL expression, the enhanced expression of Bax and Bak
(Kuo & Lin, 2003; Lee et al., 2005; Selvendiran et al., 2006) and the modulation of nuclear factor NFκB (Gong et al., 2003). Polyphenols also exhibit chemosensitizing, radiosensitizing, and radioprotective
activities (Jagetia et al., 2008).
ARISTOLOCHIA TAGALA AND CURCUMA CAESIA MITIGATES
THE EFFECT OF DIETHYLNITROSAMINE IN MICE
Aristolochia tagala Cham. (AT) known as Khur thlong in the Khasi dialect belonging to the family
Aristolochiaceae is widely distributed in India, Sri Lanka, China, Malaysia, Burma, Java, and Australia
(Murugan et al., 2006). It is one of the important medicinal plants found in Meghalaya which is part
of the Indo-Burma biodiversity hotspot and is used by the people of this region for primary health care
(Tandon et al., 2008; Singh, 2010). The roots of this plant are used by herbal practitioners for a wide
range of disorders. Different parts of A. tagala have been reported to have antimicrobial propertities,
inhibit cell proliferation, as insecticides, as pain modulators (Dey & De 2012; Latha et al., 2015). Some
phytochemicals and compounds have been identified from this plant with potential pharmacological
activities (Deepaa et al., 2010; Battu et al., 2011; Remya et al., 2016; Hadem & Sen 2018a; 2018b).
The anticancer/antitumor activity of A. tagala has also been reported by Angeles et al. (1970), Garg et
al. (2007) against KB and Anilkumar et al. (2014) against different cancer cell lines.
Curcuma caesia Roxb. (CC), commonly known as black turmeric due to the bluish black colour of
the rhizome is widely found in the Himalayan region, Northeast, and Central India. The ethanomedical
uses of C. caesia was for the treatment of cough, asthma, wounds, inflammation, stomachache, dysentery,
fever, etc. (Kala, 2005; Basak et al., 2010; Pfoze et al., 2012;). C. caesia has a wide range of biological
and pharmacological activity. It is reported to have anti-asthmatic, neuropharmacological, antidepressant,
antiulcer, nephroprotective, antimutagenic, thrombolytic activities (Arulmozhi et al., 2006; Karmakar
et al., 2011a; 2011b; Bordoloi et al., 2012; Maurya et al., 2014; Devi et al., 2015; Fathima et al., 2015)
and have shown to possess high antioxidant properties (Dhal et al., 2012; Reenu et al., 2015). Curcuma
caesia contains many essential oil and compounds with biological property (Mukunthan et al., 2014;
Chaturvedi et al., 2019; Al-Amin et al., 2019; Kumar et al., 2020). Essential oil from the leaves of C. caesia
was shown to possess antibacterial properties against Bacillus subtilis, Bacillus cereus, Staphylococcus
aureus and Salmonella typhimurium; and antifungal effect against Aspergillus fumigatus, Aspergillus
niger, Saccharomyces cerevisiae and Candida albicans (Borah et al., 2019). The anti-cancer activity of
C. caesia was evaluated in different human cancer cell lines. It was reported to have anti-proliferative
activity against (MCF-7) human breast cancer, (HCT-116) human colon cancer, (PA-1) ovarian cancer
and (DU-145) prostate cancer (Shaikh et al., 2016; Liu et al., 2013). The antitumor activity of C. caesia
was also reported against Ehrlich’s ascites carcinoma (EAC)-treated mice. The compound curcuzederone isolated from the rhizomes of the plant was found to inhibit migration of MDA-MB-231 cell line
(Al-Amin et al., 2019).
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Anticancer Eect of Aristolochia tagala and Curcuma caesia Acting Through Tumor Necrosis Factor-α
Figure 6. Aristolochia tagala and Curcuma caesia in their natural habitat.
From the study conducted by the authors, the anticancer property of A. tagala and C. caesia in DEN
induced HCC of mice was evident morphologically where the plants was able to reduce the number of
preneoplastic nodules formed when the animals were administered with DEN for prolonged period of
16-28 weeks. Structural change such as irregular cell shape, irregular nuclear shape and fragmented
nuclei which were observed in H&E liver sections of DEN induced mice were reduced in liver section of
animals treated with plant extracts of A. tagala and C. caesia (Hadem et al., 2014). The elevated activity
of marker enzymes such as AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP
(alkaline phospatase) and AChE (Acetylcholine esterase) caused by DEN induction was attenuated by
the plant extracts (Hadem et al., 2014). Relatively, the protective effect C. caesia was more consistent
than A. tagala. These enzymes are markers in diagnosis of liver injury and functional integrity of the
membrane and in HCC since they are expressed by most tumors and rapidly dividing cells (Plaa &Hewitt,
1989; Frederiks et al., 1990; Zakut et al., 1990; Soreq et al., 1991; Tarao et al., 1999). Lipid peroxidation and membrane damage caused by DEN resulted in the liberation of these enzymes into serum. C.
caesia and A. tagala might have been able to reduce the effect of DEN by protecting membrane integrity
thereby decreasing enzyme leakage.
DEN-induced inflammatory response seen by an increase in TNF-α level was reduced by treatment
with the extracts of both plants. Maeda et al. (2005) and others also reported that there was a rapid accumulation of TNF-α upon DEN administration. As mentioned, DEN was known to primarily affect
liver tissue and cause hepatocyte death (Cayama et al., 1978; Lim, 2002; Karin, 2006). Kupffer cells
activation by products such as HMGB1 and IL 1-α released by dying hepatocytes is a well-established
proinflammatory mechanism (Scaffidi et al., 2002; Maeda et al., 2005; Naugler et al., 2007; Sakurai et
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377